Breast cancer accounts for 26 annual deaths per 100,000 women in the United States and the rising incidence is a serious concern among women of all ages. Soy foods, which contain high concentrations of isoflavones, might protect against breast cancer, but the potential preventive benefit of isoflavones against breast cancer and the safety of administering isoflavones to high-risk women are not well understood. Mammographic density has been shown to be an excellent marker for breast cancer risk. Hormone replacement therapy, in particular progesterone, increases breast densities, whereas tamoxifen therapy decreases densities. The goal of the proposed project is to determine the relationship between isoflavone supplementation and mammographic densities using the mammograms collected from 406 postmenopausal women who participated in a 2-year multi-site, randomized, double-blind, and placebo-controlled study, the Osteoporosis Prevention Using Soy (OPUS) study. In the OPUS study, the women were randomized so that 1/3 of the women receive 80 mg/d of aglycone soy isoflavones, 1/3 receive 120 mg/d of aglycone soy isoflavones, and the remaining 1/3 receive a placebo for 2 years. Screening mammograms and blood concentrations of isoflavones and their metabolites measured by sensitive quadruple mass spectrometry were obtained at baseline and after 12 and 24 months of treatment. After scanning the mammograms films at the Cancer Research Center of Hawaii using a Kodak LS85 Film Digitizer, breast density will be assessed using a computer-assisted quantitative method. The reader will be blinded to the group assignment of the subjects and the time sequence of the mammograms. A random sample of films will be read in duplicate for quality control. The statistical analysis will apply general linear models to compare mammographic measures by treatment group, while considering the repeated measures. The project will provide critical information, based on data collected from the largest follow-up study with the highest isoflavone exposure, to document the relation between isoflavone supplementation and mammographic density in postmenopausal women. With the consumption of soy at record high in the United States, the proposed project will provide the much needed scientific data to the public on the safety of soy isoflavone supplementation against breast cancer. [unreadable] [unreadable] [unreadable]